CTGF is a 36 kD cysteine-rich, heparin binding, secreted glycoprotein originally isolated from the culture media of human umbilical vein endothelial cells. See e.g., Bradham et al. J Cell Biol. (1991) 114; 1285-1294; Grotendorst and Bradham, U.S. Pat. No. 5,408,040. CTGF promotes the proliferation and chemotaxis of various cell types in culture. Additionally, CTGF increases steady-state transcription of α1(I) collagen, α5 integrin, and fibronectin mRNAs. See e.g., Frazier et al. J Invest Dermatol. (1996) 107:406-411; Shi-wen et al. Exp Cell Res. (2000) 259:213-224; Klagsburn Exp Cell Res. (1977) 105:99-108; Gupta et al. Kidney Int. (2000) 58:1389-1399; Wahab et al. Biochem J. (2001) 359(Pt 1):77-87; Uzel et al. J Periodontol. (2001) 72:921-931; and Riser and Cortes Ren Fail. (2001) 23:459-470.
Through the promotion of cellular chemotaxis and proliferation along with an increase in expression of extracellular matrix (ECM) components, CTGF plays a role in regulating skeletal development, wound healing, ECM remodeling, fibrosis, tumorigenesis and angiogenesis. For example, elevated CTGF expression has been observed in cirrhotic liver, pulmonary fibrosis, inflammatory bowel disease, sclerotic skin and keloids, desmoplasia and atherosclerotic plaques. Abraham et al. J Biol Chem. (2000) 275:15220-15225; Dammeier et al. Int. J Biochem Cell Biol. (1998) 30:909-922; diMola et al. Ann Surg. (1999) 230(1):63-71; Igarashi et al. J Invest Dermatol. (1996) 106:729-733; Ito et al. Kidney Int. (1998) 53:853-861; Williams et al. J. Hepatol. (2000) 32:754-761; Clarkson et al. Curr Opin Nephrol. Hypertens. (1999) 8:543-548; Hinton et al. Eye. (2002): 16:422-428; Gupta et al. Kidney Int. (2000) 58:1389-1399; Riser et al. J Am Soc Nephrol. (2000) 11:25-38.
CTGF is also upregulated in glomerulonephritis, IgA nephropathy, focal and segmental glomerulosclerosis and diabetic nephropathy. See, e.g., Riser et al. J Am Soc Nephrol. (2000) 11:25-38. An increase in the number of cells expressing CTGF mRNA is also observed at sites of chronic tubulointerstitial damage, with CTGF mRNA levels correlated with the degree of damage. Ito et al. Kidney Int. (1998) 53:853-861. Additionally, CTGF expression is increased in the glomeruli and tubulointerstium in a variety of renal diseases in association with scarring and sclerosis of renal parenchyma. Elevated levels of CTGF have also been associated with liver fibrosis, myocardial infarction, and pulmonary fibrosis. For example, in patients with idiopathic pulmonary fibrosis (IPF), CTGF is highly enriched in biopsies and bronchoalveolar lavage cells. (Ujike et al. Biochem Biophys Res Commun. (2000) 277:448-454; Abou-Shady et al. Liver. (2000) 20:296-304; Williams et al. J Hepatol. (2000) 32:754-761; Ohnishi et al. J Mol Cell Cardiol. (1998) 30:2411-22; Lasky et al. Am J Physiol. (1998) 275: L365-371; Pan et al. Eur Respir J. (2001) 17:1220-1227; and Allen et al. Am J Respir Cell Mol Biol. (1999) 21:693-700) Thus, CTGF represents a valid therapeutic target in disorders, such as those described above.
Given the prevalence and severity of CTGF-associated diseases and disorders, there is clearly a need for improved methods of treatment that can modulate CTGF expression. Antisense oligonucleotides represent exceptional therapeutic agents based on their target specificity. The present invention discloses antisense oligonucleotide compositions and methods of use for modulating CTGF expression that can meet these therapeutic needs.